The present invention provides an efficient process for the preparation of beta amino acid derivatives of structural formula I:
    enantiomerically enriched at the carbon atom marked with an *; wherein    Z is OR2, SR2, or NR2R3;    R1 is C1-8 alkyl, aryl, heteroaryl, aryl-C1-2 alkyl, or heteroaryl-C1-2 alkyl;    R2 and R3 are each independently hydrogen, C1-8 alkyl, aryl, or aryl-C1-2 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring system optionally containing an additional heteroatom selected from O, S, N, NH, and NC1-4 alkyl, said heterocyclic ring being unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, C1-4 alkoxy, and C1-4 alkyl wherein alkyl and alkoxy are unsubstituted or substituted with one to five fluorines; and said heterocyclic ring system being optionally fused with a 5- to 6-membered saturated or aromatic carbocyclic ring system or a 5- to 6-membered saturated or aromatic heterocyclic ring system containing one to three heteroatoms selected from O, S, N, NH, and NC1-4 alkyl, said fused ring system being unsubstituted or substituted with one to four substituents selected from hydroxy, amino, fluorine, C1-4 alkyl, and C1-4 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five fluorines.
The process of the present invention relates to a method for the preparation of chiral beta amino acid derivatives of structural formula I in an efficient enantioselective fashion via rhodium metal-catalyzed asymmetric hydrogenation of a prochiral enamine of structural formula II:
in the presence of a chiral mono- or bisphosphine ligand, with the provisos that    (1) the chiral bisphosphine ligand is not a ferrocenyl bisphosphine ligand of structural formula III:
    wherein R4 is C1-4 alkyl or aryl;    R5 and R6 are each independently C1-6 alkyl, C5-12 cycloalkyl, or aryl; and    R7 is C1-4 alkyl or unsubstituted phenyl; and    (2) the chiral bisphosphine ligand is not a ligand selected from the group consisting of:    1,2-bis(anisylphenylphosphino)ethane (DIPAMP);    1,2-bis(alkylmethylphosphino)ethane (BisP*);    2,3-bis(diphenylphosphino)butane (CHIRAPHOS);    1,2-bis(diphenylphosphino)propane (PROPHOS);    2,3-bis(diphenylphosphino)-5-norbornene (NORPHOS);    2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis-(diphenylphosphino)butane (DIOP);    1-cyclohexyl-1,2-bis(diphenylphosphino)ethane (CYCPHOS);    1-substituted-3,4-bis(diphenylphosphino)pyrrolidine (DEGPHOS);    2,4-bis(diphenylphosphino)pentane (SKEWPHOS);    1,2-bis(substituted phospholano)benzene (DuPHOS);    1,2-bis(substituted phospholano)ethane (BPE);    1-(substituted phospholano)-2-(diphenylphosphino)benzene (UCAP-Ph);    1-(bis(3,5-dimethylphenyl)phosphino)-2-(substituted phospholano)benzene (UCAP-DM);    1-(substituted phospholano)-2-(bis(3,5-di(t-butyl)-4-methoxyphenyl)phosphino)benzene (UCAP-DTBM);    1-(substituted phospholano)-2-(di-naphthalen-1-yl-phosphino)benzene (UCAP-(1-Nap));    2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP);    2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl (TOL-BINAP);    2,2′-bis(di(3,5-dimethylphenyl)phosphino)-1,1′-binaphthyl (DM-BINAP);    2,2′-bis(diphenylphosphino)-6,6′-dimethyl-1,1′-biphenyl (BICHEP);    ((5,6),(5′,6′)-bis(methylenedioxy)biphenyl-2,2′-diyl)(bisdiphenylphosphine) (SEGPHOS);    ((5,6),(5′,6′)-bis(methylenedioxy)biphenyl-2,2′-diyl)(bis(3,5-dimethylphenyl)phosphine) (DM-SEGPHOS);    ((5,6),(5′,6′)-bis(methylenedioxy)biphenyl-2,2′-diyl)(bis(3,5-di(t-butyl)phenyl)phosphine) (DTBM-SEGPHOS);    cyclohexylanisylmethylphosphine (CAMP);    1-[1′,2-bis(diphenylphosphino)ferrocenyl]ethylamine (BPPFA);    1-[1′,2-bis(diphenylphosphino)ferrocenyl]ethyl alcohol (BPPFOH);    2,2′-bis(diphenylphosphino)-1,1′-dicyclopentane (BICP); and    2,2′-bis(diphenylphosphino)-1,1′-(5,5′,6,6′,7,7′,8,8′-octahydrobinaphthyl (H8-BINAP).
Methods for asymmetrically reducing enamine carbon-carbon double bonds (C═C—N) using chiral ferrocenyl bisphosphines as ligands complexed to a rhodium or iridium metal species have been described in the patent literature (See U.S. Pat. No. 5,563,309 issued Oct. 8, 1996 to Ciba-Geigy Corp. and the related family of patents and patent applications). A related approach to N-acylated beta amino acids using a rhodium DuPHOS catalytic complex has also been disclosed (See U.S. Pat. No. 6,492,544, assigned to Degussa AG). The following publications also describe the asymmetric hydrogenation of N-acylated beta-amino acrylic acids with rhodium metal species complexed to a chiral phosphine ligand: (1) T. Hayashi, et al., Bull. Chem. Soc. Japan, 53: 1136-1151 (1980); (2) G. Zhu et al., J. Org. Chem., 64: 6907-6910 (1999); (3) W. D. Lubell, et al., Tetrahedron: Asymmetry, 2: 543-554 (1991); and (4) U.S. Pat. No. 6,492,544 (assigned to Degussa AG). In these references all the examples provided have the enamine amino group in the beta-amino acrylic acid substrate for the reaction protected as an acylated derivative. The requirement for amine protection introduces two additional chemical steps into the sequence, namely protection and deprotection, and the synthesis of the protected substrate may also be difficult. The process of the present invention circumvents the need for protecting the amino group in the substrate for the asymmetric hydrogenation reaction and proceeds with excellent reactivity and enantioselectivity.
A process for the preparation of optically active piperazine-2-carboxylic acid derivatives using a metallocenylphosphine ligand has been disclosed in U.S. Pat. No. 5,886,181 (assigned to Lonza, Ltd.).
The product chiral beta-amino acid derivatives are frequent constituents of drug candidates and biologically active peptides which exhibit antibiotic, antifungal, cytotoxic, and other pharmacological properties. They are therefore commonly employed as chiral building blocks in organic synthesis [see G. Cardillo and C. Tomasini, Chem. Soc. Rev., 117-128 (1996)]. Another important application is the substitution of unnatural alpha- and beta-amino acids in biologically active peptides, which greatly enhance the understanding of enzyme mechanisms, protein conformations and properties related to molecular recognition, and for obtaining peptides with increased potency and enzymatic stability.